PT  - JOURNAL ARTICLE
AU  - Matthew N. Hill
AU  - Ryan J. McLaughlin
AU  - Bin Pan
AU  - Megan L. Fitzgerald
AU  - Christopher J. Roberts
AU  - Tiffany T.-Y. Lee
AU  - Ilia N. Karatsoreos
AU  - Ken Mackie
AU  - Victor Viau
AU  - Virginia M. Pickel
AU  - Bruce S. McEwen
AU  - Qing-song Liu
AU  - Boris B. Gorzalka
AU  - Cecilia J. Hillard
TI  - Recruitment of Prefrontal Cortical Endocannabinoid Signaling by Glucocorticoids Contributes to Termination of the Stress Response
AID  - 10.1523/JNEUROSCI.0496-11.2011
DP  - 2011 Jul 20
TA  - The Journal of Neuroscience
PG  - 10506--10515
VI  - 31
IP  - 29
4099  - http://www.jneurosci.org/content/31/29/10506.short
4100  - http://www.jneurosci.org/content/31/29/10506.full
SO  - J. Neurosci.2011 Jul 20; 31
AB  - The mechanisms subserving the ability of glucocorticoid signaling within the medial prefrontal cortex (mPFC) to terminate stress-induced activation of the hypothalamic–pituitary–adrenal (HPA) axis are not well understood. We report that antagonism of the cannabinoid CB1 receptor locally within the mPFC prolonged corticosterone secretion following cessation of stress in rats. Mice lacking the CB1 receptor exhibited a similar prolonged response to stress. Exposure of rats to stress produced an elevation in the endocannabinoid 2-arachidonoylglycerol within the mPFC that was reversed by pretreatment with the glucocorticoid receptor antagonist RU-486 (20 mg/kg). Electron microscopic and electrophysiological data demonstrated the presence of CB1 receptors in inhibitory-type terminals impinging upon principal neurons within layer V of the prelimbic region of the mPFC. Bath application of corticosterone (100 nm) to prefrontal cortical slices suppressed GABA release onto principal neurons in layer V of the prelimbic region, when examined 1 h later, which was prevented by application of a CB1 receptor antagonist. Collectively, these data demonstrate that the ability of stress-induced glucocorticoid signaling within mPFC to terminate HPA axis activity is mediated by a local recruitment of endocannabinoid signaling. Endocannabinoid activation of CB1 receptors decreases GABA release within the mPFC, likely increasing the outflow of the principal neurons of the prelimbic region to contribute to termination of the stress response. These data support a model in which endocannabinoid signaling links glucocorticoid receptor engagement to activation of corticolimbic relays that inhibit corticosterone secretion.